1a. Objectives (from AD-416)
LAB: Bone Health 1. Conduct clinical studies to determine the effects of vitamin D in the prevention of physical dysfunction, oral disease, and diabetes, and other chronic diseases in older adults. 2. Conduct clinical studies to determine the effects of dietary protein and dietary acid-base balance on bone and muscle metabolism and function, respectively, in older adults. 3. Determine the role and mechanisms of action for calcium, magnesium, and other dietary components in the maintenance of bone health and the progression of related diseases. LAB: Vitamin K 1. Determine the amounts of individual dietary forms of vitamin K in nationally representative samples of frequently consumed U.S. foods and dietary supplements. 2. Characterize the effects of dietary and non-dietary factors, such as age, lipid profile and body fat, on the bioavailability and utilization of different forms of vitamin K in humans. 3. Identify mechanisms of action for vitamin K, other than its classic role as an enzyme cofactor, using cellular and animal models.
1b. Approach (from AD-416)
LAB: Bone Health The Bone Metabolism Laboratory uses a variety of approaches to carry out its clinical and translational research program. Observational studies such as the publicly available cross-sectional National Health and Nutrition Examination Survey will be used to examine associations of vitamin D with bone mineral density. Longitudinal cohort studies, such as the Nurses Health Study, will be used to link vitamin D levels to risk of several chronic diseases. We will employ diet-controlled metabolic studies to define address several research goals. For example, we will examine the impact of a dietary alkaline load on muscle tissue changes and on indices of bone metabolism in healthy older subjects on both low and high protein diets. Information learned from this metabolic study will be helpful in the design of a large randomized controlled trial to determine the long term effects of lowering the dietary acid load on muscle performance and mass and on rates of bone turnover and bone loss. The Bone Metabolism Laboratory has a strong network of collaborations, both internal, exemplified by our work on multiple projects with the Nutrition, Exercise Physiology and Sarcopenia Laboratory, and external. These collaborations allow us to expand our reach to examine the effect of vitamin D on risk of other chronic diseases such as periodontal disease and diabetes. They also allow us access to basic research technologies, such as gene array analysis, that enable us to identify mechanisms by which nutrients affect bone and muscle. LAB: Vitamin K Laboratory analysis of different forms of vitamin K will be conducted in selected foods obtained through collaboration with the USDA Nutrient and Data Laboratory (NDL), as part of the Food and Nutrient Analysis Program. Priorities for food analysis will include dietary supplements, food purchased in family style restaurants, foods common to the Hispanic/Latino diet, and foods associated with high calorie diets. Food composition data will be transferred to the NDL for entry into national food composition databases. To identify dietary and non-dietary factors that determine how much vitamin K obtained from foods is utilized, we will apply stable isotope techniques to measures of vitamin K metabolism. Data obtained from ongoing metabolic studies in men and women, in addition to pilot feasibility studies, will be used to refine the study design to test the response of these measures to intake of different vitamin K-rich food sources. Animal models will be used to identify tissue-specific effects of interactions between vitamin K and other fat-soluble vitamins, with an emphasis on vitamins A and D. To identify mechanisms of action for vitamin K other than its classic role as an enzyme cofactor, urinary and serum levels of vitamin K metabolites will be measured in response to vitamin K supplementation using archived samples from human and animal studies. We will then focus on the role of different forms of vitamin K in inflammation through the inactivation of nuclear receptors in macrophages.
3. Progress Report
This project includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with Tufts University. For further information and progress reports, see 1950-51000-069-01S, (Musculoskeletal Health in the Elderly) and 1950-51000-069-02S, (Vitamin K: Food Composition, Bioavailability and its Role in Human Health).
1. Vitamin D supplementation is associated with reduced risk of falling (LAB: Bone Health). Vitamin D insufficiency increases risk of falling in older adults. ARS-funded researchers from Tufts University in Boston, MA recently completed and published a meta-analysis of the available data from randomized controlled trials that assessed the effect of supplemental vitamin D versus placebo on risk of falling in older men and women. Eight trials involving more than 2,426 subjects were included in the analysis. We found that doses of vitamin D in the range of 700 – 1000 IU/d lowered risk of falling by an average of 20%; lower doses in the range of 200-600 IU per day had no significant effect on risk of falling. This work suggests that correction of widespread vitamin D deficiency is likely to be an effective strategy to reduce falls in older adults.
2. Supplemental vitamin D and home-based exercise reduce falls in subjects with recent hip fracture (LAB: Bone Health). Falls are a major cause of fractures and other injuries in the elderly. ARS-funded researchers from Tufts University in Boston, MA recently collaborated with scientists in Switzerland to complete a randomized controlled trial in 173 elders with recent hip fractures. The study revealed that supplementation with vitamin D (2000 compared with 800 IU) lowered the number of injurious falls and the numbers of hospital admissions for infection in the year following the hip fracture. A moderately vigorous home-based exercise program significantly lowered risk of falling in the same subjects, when compared with the standard of care, no exercise training or advice. It appears that the combination of 2000 IU per day of supplemental vitamin D and training in home-based exercises along with advice to exercise for 30 minutes per day have complementary effects on lowering risk of falling in the elderly. These interventions were safe and well tolerated and should be evaluated in other populations for their ability to lower risk of falling.
3. Poor vitamin D status is associated with poorer cognitive function (LAB: Bone Health). Impaired cognitive function with aging is a serious and growing problem in the U.S. ARS-funded researchers from Tufts University in Boston, MA completed a study of the association of vitamin D status with mental function in a large group of homebound elders. They demonstrated that serum 25-hydroxyvitamin D levels are positively associated with several components of mental function, including executive function and mental processing speed. These findings provide preliminary data needed to design intervention studies of vitamin D supplementation to improve mental function in older adults.
4. Potassium bicarbonate enhances the impact of protein on muscle (LAB: Bone Health). Dietary protein is essential for muscle health, but less is known about how the overall composition of the diet may influence the effect of protein on muscle. ARS-funded researchers from Tufts University in Boston, MA investigated the muscle effects of dietary protein in combination with potassium bicarbonate (to neutralize the acid load of the protein). They demonstrated that this combination increases serum insulin-like growth factor 1 (IGF-1) and reduces levels of nitrogen in the urine. These findings suggest that the favorable effects of dietary protein on muscle may be enhanced by neutralizing the acid load that accompanies high protein diets.
5. Hypertension is a major health problem in the elderly and vitamin D insufficiency may be a contributing factor. (LAB: Bone Health). ARS-funded researchers from Tufts University in Boston, MA, in collaboration with researchers at Michigan State University completed a crosssectional study of the association of vitamin D deficiency with hypertension in uninsured women. The subjects were 18 to 64 years old and were patients at a County Free Clinic in urban Michigan. Vitamin D status, as indicated by serum 25OHD measurements, was inversely associated with hypertension prevalence and with both systolic and diastolic blood pressure. These findings suggest that improving vitamin D status may help to prevent hypertension in the vulnerable uninsured population.
6. Body Fat Stores Vitamin K and Reduces Its Availability for Important Body Functions (LAB: Vitamin K). It has been proposed that overweight and obese people store fat-soluble vitamins in their fat cells, and this storage can decrease these nutrients’ contribution to health. In contrast to vitamins A, D, and E, and carotenoids, little is known about the role of body fat in changing vitamin K functions. ARS-funded researchers from Tufts University in Boston, MA determined that vitamin K is stored in body fat. Furthermore, more body fat was associated with less vitamin K available to other organs. Moderate weight loss did not result in an improvement in vitamin K status. These findings suggest that obesity may attenuate the contribution of dietary vitamin K to human health.
Ettinger, B., Black, D., Dawson-Hughes, B., Pressman, A.R., Melton, L. 2010. Updated fracture incidence rates for the US version of FRAX (registered trademark). Osteoporosis International. 21:25-33.
Crosier, M.D., Peter, I., Booth, S.L., Bennett, G., Dawson-Hughes, B., Ordovas, J.M. 2009. Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylas genes with biochemical measures of vitamin K status. Journal of Nutritional Science and Vitaminology. 55:112-119.
Durazo-Arvizu, R.A., Dawson-Hughes, B., Sempos, C.T., Yetley, E.A., Looker, A.C., Cao, G., Harris, S.S., Burt, V.L., Carriquiry, A.L., Picciano, M. 2010. Three-Phase Model Harmonizes Estimates of the Maximal Suppression of Parathyroid Hormone by 25-Hydroxyvitamin D in Persons 65 Years of Age and Older 1–3. Journal of Nutrition. 140(3):595-599.
Dawson-Hughes, B., Harris, S. 2010. Vitamin D recommendations for older adults. Journal of the American Medical Association. 303(18):1861-1862.
Dawson-Hughes, B., Mthal, A., Bonjour, J., Boonen, S., Burckhardt, P., El-Hadjj Fuleihan, G., Josse, R.G., Lips, P., Torres, J., Yoshimura, N. 2010. Vitamin D recommendations for older adults. In: Johnson, T., editor. Osteoporosis International. 7th edition. London, England: Springer London. p.1151-1154.
Shea, M., Gundberg, C., Meigs, J., Dallal, G., Saltzman, E., Yoshida, M., Jacques, P., Booth, S.L. 2009. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. American Journal of Clinical Nutrition. 90(5):1230-1235.
Booth, S.L. 2009. Roles for vitamin K beyond coagulation. Annual Reviews of Nutrition. 29:89-110.
Fu, X., Peterson, J.W., Hdeib, M., Booth, S.L., Grusak, M.A., Lichtenstein, A.H., Dolnikowski, G. 2009. Measurement of deuterium-labeled phylloquinone in plasma by high-performance liquid chromatography/mass spectrometry (LC/MS). Analytical Chemistry. 81:5421-5425.
Cheng, S., Massaro, J., Fox, C., Larson, M., Keyes, M., Mccabe, E., Robins, S., O'Donnell, C., Hoffman, U., Jacques, P., Booth, S.L., Vasan, R., Wolf, M., Wang, T. 2010. Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart Study. Diabetes. 59:242-248.
Holden, R.M., Morton, R.A., Garland, J.S., Booth, S.L. 2010. Vitamins K and D status in patients with stages 3-5 chronic kidney disease. Journal of the American Society of Nephrology. 5(4):590-597.
Shea, K., Booth, S.L., Gundberg, C.M., Peterson, J.W., Waddell, C., Dawson-Hughes, B., Saltzman, E. 2010. Adulthood obesity is positively associated with adipose tissue concentrations of vitamin K and inversely associated with circulating indicators of vitamin K status in men and women. Journal of Nutrition. 140:1029-1034.
Booth, S.L. 2010. Dietary vitamin K guidance: an effective strategy for stable control of oral anticoagulation?. Nutrition Reviews. 68(3):178–181.